Effect of dietary fat and sucrose consumption on cardiac fibrosis in mice and rhesus monkeys.
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ABSTRACT:
SUBMITTER: Natarajan N
PROVIDER: S-EPMC6795382 | biostudies-literature | 2019 Sep
REPOSITORIES: biostudies-literature
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Effect of dietary fat and sucrose consumption on cardiac fibrosis in mice and rhesus monkeys.
Natarajan Niranjana N Vujic Ana A Das Jishnu J Wang Annie C AC Phu Krystal K KK Kiehm Spencer H SH Ricci-Blair Elisabeth M EM Zhu Anthony Y AY Vaughan Kelli L KL Colman Ricki J RJ Mattison Julie A JA Lee Richard T RT
JCI insight 20190919 18
Calorie restriction (CR) improved health span in 2 longitudinal studies in nonhuman primates (NHPs), yet only the University of Wisconsin (UW) study demonstrated an increase in survival in CR monkeys relative to controls; the National Institute on Aging (NIA) study did not. Here, analysis of left ventricle samples showed that CR did not reduce cardiac fibrosis relative to controls. However, there was a 5.9-fold increase of total fibrosis in UW hearts, compared with NIA hearts. Diet composition w ...[more]
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Project description:Purpose: Obesity is a global health issue. To investigate if protein and fat contents of the diets had effects on energy balance via the canonical hunger signaling pathways in the hypothalamus, RNAseq was performed on RNA extracted from the hypothalami of mice exposed to the different diets. A suggested mechanism by which animals may avoid obesity is by burning off excess energy via upregulation of white adipose tissue (WAT) browning. To investigate if protein and fat content of the diet had effects on energy balance via the browning related signaling pathways in the WAT, RNAseq was performed on RNA extracted from the subcutaneous WAT (sWAT) and epididymal WAT (eWAT) of mice exposed to the different diets. Methods: C57BL/6 male mice were used in this work. All mice were fed a standard diet with 10% fat and 20% protein (D12450B, Research Diets Ltd) for 2 weeks as the baseline period. 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WAT gene expression showed decrease in expression of general thermogenic related genes and WAT browning related genes in relation to both dietary protein and dietary fat, while Tgfb1, Pdk4 and Fgf1 were all upregulated in relation to dietary fat levels. Conclusions: Significant positive associations were evident between the fat levels of the diet and the main hedonic signaling systems linked to food intake. Significant negative associations were found between both protein and fat levels of the diet and WAT browning or general thermogenic signalings linked to energy expenditure.
2018-05-29 | GSE114960 | GEO
Project description:Excess caloric intake is strongly associated with the development of increased adiposity, glucose intolerance, insulin resistance, dyslipidemia, and hyperleptinemia (that is the cardiometabolic syndrome). Research efforts have focused attention primarily on the quality (that is nutritional content) and/or quantity of ingested calories as potential causes for diet-induced pathology. Despite growing acceptance that biological rhythms profoundly influence energy homeostasis, little is known regarding how the timing of nutrient ingestion influences development of common metabolic diseases.To test the hypothesis that the time of day at which dietary fat is consumed significantly influences multiple cardiometabolic syndrome parameters.We report that mice fed either low- or high-fat diets in a contiguous manner during the 12? h awake/active period adjust both food intake and energy expenditure appropriately, such that metabolic parameters are maintained within a normal physiologic range. In contrast, fluctuation in dietary composition during the active period (as occurs in human beings) markedly influences whole body metabolic homeostasis. Mice fed a high-fat meal at the beginning of the active period retain metabolic flexibility in response to dietary challenges later in the active period (as revealed by indirect calorimetry). Conversely, consumption of high-fat meal at the end of the active phase leads to increased weight gain, adiposity, glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and hyperleptinemia (that is cardiometabolic syndrome) in mice. The latter perturbations in energy/metabolic homeostasis are independent of daily total or fat-derived calories.The time of day at which carbohydrate versus fat is consumed markedly influences multiple cardiometabolic syndrome parameters.
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Project description:Variation at the human mu-opioid receptor has been associated with alcohol abuse. The A118G (N40D) polymorphism in humans is functionally mimicked by the C77G (P26R) polymorphism in rhesus monkeys; both show similar in vitro influences on ligand binding and in vivo correlations with physiological measures as well as behavioral measures including predilection towards alcohol consumption. Naltrexone, an antagonist at the receptor, has been used to treat alcoholism in humans and has been reported to show differences in effectiveness depending on genotype.Here we describe a study in which we a priori selected rhesus monkeys based on genotype at the OPRM1 C77G single nucleotide polymorphism, trained them to self-administer alcohol, and assessed naltrexone responsiveness.Alcohol intake in rhesus monkeys varied with genotype across a range of alcohol concentrations (0.5-4%, w/v) such that animals with the G/G genotype drank consistently more alcohol than those animals with the C/C genotype. Additionally, naltrexone attenuated alcohol drinking in a dose- and genotype-dependent manner. Animals harboring the G/G genotype were more sensitive to the effects of naltrexone and showed greater reductions in alcohol consumption at lower naltrexone doses compared to animals with a C/G or C/C genotype.This preliminary study demonstrates a pharmacogenomic response to naltrexone in rhesus monkeys that parallels that seen in humans. This finding provides a basis for developing a pharmacogenetic animal model for naltrexone effect that can expand further our understanding of the causes and treatments of alcohol use disorders.
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Project description:BackgroundA paucity of information on biological sex-specific differences in cardiac gene expression in response to diet has prompted this present nutrigenomics investigation. Sexual dimorphism exists in the physiological and transcriptional response to diet, particularly in response to high-fat feeding. Consumption of Trans-fatty acids (TFA) has been linked to substantially increased risk of heart disease, in which sexual dimorphism is apparent, with males suffering a higher disease rate. Impairment of the cardiovascular system has been noted in animals exposed to Monosodium Glutamate (MSG) during the neonatal period, and sexual dimorphism in the growth axis of MSG-treated animals has previously been noted. Processed foods may contain both TFA and MSG.MethodsWe examined physiological differences and changes in gene expression in response to TFA and/or MSG consumption compared to a control diet, in male and female C57BL/6J mice.ResultsHeart and % body weight increases were greater in TFA-fed mice, who also exhibited dyslipidemia (P < 0.05). Hearts from MSG-fed females weighed less than males (P < 0.05). 2-factor ANOVA indicated that the TFA diet induced over twice as many cardiac differentially expressed genes (DEGs) in males compared to females (P < 0.001); and 4 times as many male DEGs were downregulated including Gata4, Mef2d and Srebf2. Enrichment of functional Gene Ontology (GO) categories were related to transcription, phosphorylation and anatomic structure (P < 0.01). A number of genes were upregulated in males and downregulated in females, including pro-apoptotic histone deacetylase-2 (HDAC2). Sexual dimorphism was also observed in cardiac transcription from MSG-fed animals, with both sexes upregulating approximately 100 DEGs exhibiting sex-specific differences in GO categories. A comparison of cardiac gene expression between all diet combinations together identified a subset of 111 DEGs significant only in males, 64 DEGs significant in females only, and 74 transcripts identified as differentially expressed in response to dietary manipulation in both sexes.ConclusionOur model identified major changes in the cardiac transcriptional profile of TFA and/or MSG-fed mice compared to controls, which was reflected by significant differences in the physiological profile within the 4 diet groups. Identification of sexual dimorphism in cardiac transcription may provide the basis for sex-specific medicine in the future.
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